Abstract Glioblastoma (GBM) is the most common malignant brain tumor and has a median survival of less than 15 months, presenting an urgent clinical challenge. To overcome this challenge, our research has focused on Methylthioadenosine phosphorylase (MTAP). MTAP deletion occurs in about half of GBM patients, suggesting any therapeutic strategy devised based on MTAP status will significantly impact the treatment landscape of this disease. Our preliminary study has demonstrated that MTAP deletion is associated with a worse clinical outcome. In studying the underlying mechanism, we have elucidated that the status of MTAP (presence or absence) affects GBM cells? DNA methylome and the expression of genes involved in GBM pathogenesis and in response to treatments. Furthermore, we have devised additional strategies of exploiting MTAP status for clinical benefit. Normally, MTAP functions in the salvage pathway for adenine and methionine. In MTAP-deficient tumor cells, the absence of this salvage pathway sensitizes cells to inhibitors of de novo purine synthesis, providing an opportunity to specifically target cancer cells. We have devised a novel purine starvation strategy that can effectively abrogate tumor growth. These exciting findings prompt us to further understand the molecular mechanism of MTAP deletion in GBM and refine the promising therapeutic approach we have developed. Our central hypothesis is that MTAP loss affects GBM progression via altering DNA methylation, and that MTAP deletion can be exploited for GBM treatment. Specific Aim 1: Determine the functional consequences of MTAP deletion in GBM. We will test the hypothesis that MTAP deletion affects GBM progression via altering cancer cells? DNA methylation patterns. Sub-Aim 1.1: Determine the mechanism underlying the effects of MTAP deletion on GBM cells; and Sub-Aim 1.2: Determine the clinical significance of MTAP deletion. Specific Aim 2: Develop a purine starvation-based therapeutic strategy for MTAP-null GBM. We will test the hypothesis that purine starvation can be an effective treatment for MTAP-null GBM. Sub-Aim 2.1: We will use xenograft models derived from primary GBM cultures and test their response to purine starvation; and Sub-Aim 2.2: We will determine the mechanism underlying GBM cells? response to purine starvation. This study will establish MTAP deletion as a direct therapeutic target in GBM, illuminate the mechanism underlying the consequences of MTAP deletion in GBM progression and response to treatment, generate novel in vitro and in vivo GBM models, and potentially lead to a new paradigm for clinical management of GBM.